This is a competing renewal application for five years of funding of a P60 Comprehensive Center with the theme of improving treatment of substance abuse. Originally the Center focused on heroin, but later expanded to include cocaine, nicotine and alcohol. The Center traces its origin to the Philadelphia VA Substance Abuse Program founded in 1971 with the intent of integrating research and treatment. The first NIH and VA grants were obtained in 1973-74 and additional investigators and related lines of research were gradually added. In 1987, NIDA center funding was obtained and a clinical research treatment program for non-veterans was founded on the Penn campus. The P60 NIDA Center now forms the umbrella for multiple NIDA, NIAID, NIAAA and VA research programs located in the Penn site as well as the VA and the nearby Presbyterian Medical Center campus of the University. An important outgrowth of the Center in 1991 was the Treatment Research Institute (TRI), a non-profit organization dedicated to technology transfer and analysis of individual substance abuse treatment programs throughout the country. While the Center has always emphasized clinical research, it has maintained some basic research activity utilizing animal models of substance abuse to screen potential medications for substance use disorders. There is an emphasis on interaction between pre-clinical and clinical investigators both among our faculty and our external advisory board. The Center also houses an extensive education program on the subject of substance abuse directed at medical students, residents, post-doctoral fellows and drug abuse counselors. This program is not limited to the University of Pennsylvania, but rather is a national resource as a Center of Excellence for the VA and for the nationwide minority fellowship program it operates. Dissemination of new technology to the treatment community has always been an important goal of the Center. This has recently been facilitated by our designation as a node in the Clinical Trials Network. In addition, the TRI has begun a national treatment monitoring initiative that will ultimately include 700 treatment programs across the country. This application consists of seven sections: 1. Core: Introduction, Structure, Educational Functions 2. Core: Research Coordination 3. Core: Biostatistics/Informatics; 4.-7. New Projects (three clinical and one preclinical).